Process for preparing 1-phenylpyrazoles

ABSTRACT

The present invention to a process for preparing 1-phenylpyrazoles of the formula I 
                         
in which each R 1  is independently selected from chlorine, fluorine, alkyl, haloalkyl, alkoxy and haloalkoxy; n is 1, 2 or 3; each R 2  is independently selected from cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio and alkoxycarbonyl; m is 0, 1 or 2; A is alkyl, aryl or aryl-C 1 -C 4 -alkyl, where A optionally bears 1, 2, 3 or 4 substituents
 
comprising reacting a phenyl halide of the formula (II) with a pyrazole derivative of the formula (III)
 
                         
in which
 
X is chlorine, iodine or bromine; and
 
R 1 , n, R 2 , m and A are each as defined above,
 
in the presence of a base and a catalytic system comprising a ligand and a metal compound selected from palladium compounds, iron compounds and copper compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/393,624, filed Mar. 1, 2012, now U.S. Pat. No. 8,362,271, whichapplication is a national stage application of International ApplicationNo. PCT/EP2010/062950, filed Sep. 3, 2010, the entire contents of whichis hereby incorporated herein by reference. This application also claimspriority under 35 U.S.C. §119 to European Patent Application No.09169528.8 filed Sep. 4, 2009, the entire contents of which is herebyincorporated herein by reference.

DESCRIPTION

The present invention relates to a process for preparing1-phenylpyrazoles. In particular, the invention relates to a process forpreparing 1-phenylpyrazoles by C—N coupling of a phenyl halide and apyrazole compound.

1-Phenylpyrazols are of great interest especially as pharmaceutical andpesticide pharmacophors, and as precursors of such active ingredients.Pyraclostrobine is a prominent representative of a pesticidalN-phenylpyrazole derivative.

The most important method for preparing this class of heterocyclesinvolves the double condensation of 1,3-diketones with phenyl hydrazineor its derivatives. This method has a wide scope not only because of thereadily availability of 1,3-diketones but also because one carbonyl ofthe diketone starting material can be replaced by an acetal, ahemiacetal, a chlorovinyl group, dihalides, etc.

Despite its versatility, the known method may require reactionconditions incompatible with many functional groups. Also,1-phenylpyrazole compounds with certain substitution patterns may not oronly with difficulties be accessible by existing methodologies.

Thus, there is an ongoing need for a process for preparing1-phenylpyrazoles by coupling larger, functionalized molecules.

Transition metal-catalyzed cross-coupling of nitrogen nucleophiles withcarbon electrophiles has emerged as a powerful tool in synthetic organicchemistry. Common electrophiles include aryl and vinyl halides,triflates and sulfonates. The nucleophiles being used comprise primaryand secondary amines, ammonia, anilines, amides and carbamates. C—Ncouplings of aromatic nitrogen heterocycles, such as pyrazoles have alsobeen investigated. C. Tironi, R. Fruttero and A. Garrone in Farmaco1990, 45 (4), p. 473-478 describe the reaction of 3-acetylaminopyrazolewith bromonitrobenzenes in the presence of potassium carbonate,copper(I) oxide and pyridine, to obtain3-acetylamino-1-(nitrophenyl)-pyrazole.

K. H. Park et al. in Kor. Chem. Soc. 16(9), p. 799-801 (1995) describethe reaction of 5-hydroxy-3-trifluoromethylpyrazole with3,4-dichloronitrobenzene in the presence of potassium carbonate indimethylformamide.1-(2-Chloro-4-nitrophenyl)-5-hydroxy-3-trifluoromethyl-pyrazole wasobtained as the main reaction product.

WO 99/62885 makes reference to a synthetic method where a3,5-disubstituted pyrazole is reacted with nitrobenzene substituted inthe 4-position with a leaving group such as a halogen in the presence ofa base.

These prior art references describe the use of aryl electrophiles wherea halogen leaving group is activated by a nitro group.

It was an object of the present invention to provide a process forpreparing 1phenylpyrazoles from phenylhalides where the phenyl ring issubstituted by substituents different from a nitro group. The processshould additionally be performable inexpensively and be based onselective conversions.

The object is achieved by the process described in detail below.

The present invention provides a process for preparing 1-phenylpyrazolesof the general formula (I)

in which

-   -   each R¹ is independently selected from chlorine, fluorine,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;    -   n is 1, 2 or 3;    -   each R² is independently selected from cyano, nitro, halogen,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₁-C₄-alkylthio and C₁-C₄-alkoxycarbonyl;    -   m is 0, 1 or 2;    -   A is C₁-C₁₂-alkyl, aryl or aryl-C₁-C₄-alkyl, where A optionally        bears 1, 2, 3 or 4 substituents which are selected from halogen,        cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,        C₁-C₄-haloalkoxy, a group R^(a), a group R^(b), a group R^(c)        and a group R^(d)

in which

-   -   R⁴ is H, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, aryl,        aryloxy, aryl-C₁-C₄-alkoxy, where the aryl groups in the three        latter radicals optionally bear 1, 2, 3 or 4 substituents which        are selected from halogen, cyano, nitro, C₁-C₄-alkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, and    -   R⁵ is C₁-C₄-alkyl, C₁-C₄-haloalkyl or aryl-C₁-C₄-alkyl, where        the aryl group in the latter radical optionally bears 1, 2, 3 or        4 substituents which are selected from halogen, cyano, nitro,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;        comprising the following step    -   (i) reacting a phenyl halide of the formula (II) with a pyrazole        derivative of the formula (III)

in which

X is chlorine, iodine or bromine; and

R¹, n, R², m and A are each as defined above;

in the presence of a base and a catalytic system comprising a ligand anda metal compound selected from palladium compounds, iron compounds orcopper compounds.

In the context of the present invention, the terms used generically aredefined as follows:

The prefix C_(x)-C_(y) denotes the number of possible carbon atoms inthe particular case.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine, especially fluorine, chlorine or bromine.

The term “C₁-C₄-alkyl” denotes a linear or branched alkyl radicalcomprising from 1 to 4 carbon atoms, such as methyl, ethyl, propyl,1-methylethyl(isopropyl), butyl, 1-methyl-propyl(sec-butyl),2-methylpropyl(isobutyl) or 1,1-dimethylethyl(tert-butyl).

The term “C₁-C₁₂-alkyl” denotes a linear or branched alkyl radicalcomprising from 1 to 12 carbon atoms. Examples are, as well as theradicals specified for C₁-C₄-alkyl, pentyl, hexyl, heptyl, octyl,2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, 2-propylheptyl,3-butyloctyl and positional isomers thereof.

The term “cycloalkyl” denotes monocyclic saturated hydrocarbon groupshaving 3 to 6 (C₃-C₆-cycloalkyl), 3 to 8 (C₃-C₈-cycloalkyl) or 3 to 10(C₃-C₁₀-cycloalkyl) carbon ring members, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyland cyclodecyl;

The term “C₁-C₄-haloalkyl”, as used herein and in the haloalkyl units ofC₁-C₄-haloalkoxy, describes straight-chain or branched alkyl groupshaving from 1 to 4 carbon atoms, where some or all of the hydrogen atomsof these groups have been replaced by halogen atoms. Examples thereofare chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,di-chlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl,1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2,2,2-trichloroethyl, pentafluoroethyl, 3,3,3-trifluoroprop-1-yl,1,1,1-trifluoroprop-2-yl, 3,3,3-trichloroprop-1-yl,heptafluoroisopropyl, 1-chlorobutyl, 2-chlorobutyl, 3-chlorobutyl,4-chlorobutyl, 1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl and the like.

The term “C₁-C₄-alkoxy” denotes straight-chain or branched saturatedalkyl groups comprising from 1 to 4 carbon atoms, which are bound via anoxygen atom to the remainder of the molecule. Examples of C₁-C₄-alkoxyare methoxy, ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy,1-methylpropoxy(sec-butoxy), 2-methylpropoxy(isobutoxy) and1,1-dimethylethoxy(tert-butoxy).

The term “C₁-C₄-haloalkoxy” describes straight-chain or branchedsaturated haloalkyl groups comprising from 1 to 4 carbon atoms, whichare bound via an oxygen atom to the remainder of the molecule. Examplesthereof are chloromethoxy, bromomethoxy, dichloromethoxy,trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy,1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy,1-chloro-1,2,2-trifluoroethoxy, pentafluoro-ethoxy,3,3,3-trifluoroprop-1-oxy, 1,1,1-trifluoroprop-2-oxy,3,3,3-trichloroprop-1-oxy, 1-chlorobutoxy, 2-chlorobutoxy,3-chlorobutoxy, 4-chlorobutoxy, 1-fluorobutoxy, 2fluorobutoxy,3-fluorobutoxy, 4-fluorobutoxy and the like.

The term “C₁-C₄-alkoxycarbonyl” denotes alkoxy radicals having from 1 to4 carbon atoms which are bound via a carbonyl group to the remainder ofthe molecule. Examples thereof are methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl.

The term “aryl” denotes carbocyclic aromatic radicals having from 6 to14 carbon atoms. Examples thereof comprise phenyl, naphthyl, fluorenyl,azulenyl, anthracenyl and phenanthrenyl. Aryl is preferably phenyl ornaphthyl, and especially phenyl.

The term “hetaryl” denotes aromatic radicals having from 1 to 4heteroatoms which are selected from O, N and S. Examples thereof are 5-and 6-membered hetaryl radicals having 1, 2, 3 or 4 heteroatoms selectedfrom O, S and N, such as pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl and triazinyl.

The term “aryl-C₁-C₄-alkyl” denotes aryl radicals which are bound via aC₁-C₄-alkyl group to the remainder of the molecule. Examples thereof arebenzyl, 2-phenylethyl(phenethyl) and the like.

The term “aryl-C₁-C₄-alkoxy” denotes aryl-C₁-C₄-alkyl radicals asdefined above which are bound via an oxygen atom to the remainder of themolecule. Examples thereof are benzyloxy, fluorenylmethoxy and the like.

The term “C₁-C₄-alkylthio “(C₁-C₄-alkylsulfanyl: C₁-C₄-alkyl-S—)”denotes straight-chain or branched saturated alkyl radicals having 1 to4 carbon atoms which are bound via a sulfur atom to the remainder of themolecule. Examples for C₁-C₄-alkylthio include methylthio, ethylthio,propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio,2methylpropylthio and 1,1-dimethylethylthio.

The remarks made below regarding preferred embodiments of the processaccording to the invention, especially regarding preferred meanings ofthe variables of the different reactants and products and of thereaction conditions of the process, apply either taken alone or, moreparticularly, in any conceivable combination with one another.

In the compounds of the formulae (I), (Ia), (II), (IV), (V) and (VI) nis preferably 0, 1 or 2 and especially preferably 0 or 1. When n is 1,R¹ is preferably in the para or meta position to the attachment point ofthe pyrazole moiety or to the 1-position of the radical X in a compoundII.

In the compounds of the formulae (I), (Ia), (II), (IV), (V) and (VI) R¹is preferably chlorine, fluorine, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxy or C₁-C₂-haloalkoxy. R¹ is more preferably chlorine,fluorine, C₁-C₂-alkyl or C₁-C₂-haloalkyl and even more preferablychlorine, methyl or halomethyl. Specifically, R¹ is 4-Cl, 3-Cl,4-methyl, 3-methyl, 2-methyl, 4-methoxy, 3-methoxy, 3-chloromethyl,4-chloromethyl, 4-trifluoromethyl, 3-trifluoromethyl, 3-chloromethoxy,4-chloromethoxy, 4-trifluoromethoxy, 3-trifluoromethoxy, 3,4-Cl₂,2,4-Cl₂, 3,4-dimethyl, 2,4-dimethyl, 3,4-dimethoxy or 2,4-dimethoxy. Thestatements of position relate to the 1-position through which the phenylradical deriving from the compound of the formula (II) is bonded to thepyrazole ring or to the 1-position of the radical X in the phenyl halideII.

In the compounds of the formulae (I), (Ia), (III), (IIIa), (IV), (V) and(VI) m is preferably 0 or 1 and especially preferably 0.

In the compounds of the formulae (I), (Ia), (III), (IIIa), (IV), (V) and(VI) R² is preferably halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, or C₁-C₂-alkoxycarbonyl. R² is morepreferably chlorine, fluorine, C₁-C₂-alkyl, C₁-C₂-haloalkyl orC₁-C₂-alkoxycarbonyl and even more preferably chlorine, fluorine,methyl, halomethyl or methoxycarbonyl.

In the compounds of the formulae (I) and (III) A is preferablyC₁-C₈-alkyl that optionally bears 1, 2, or 3 substituents selected fromhalogen, C₁-C₄-alkoxy, C₁-C₂-haloalkoxy, a group R^(a), a group R^(b), agroup R^(c) and a group R^(d), or aryl-C₁-C₂-alkyl that optionally bears1, 2 or 3 substituents which are selected from nitro, halogen,C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, a groupR^(a), a group R^(b), a group R^(c) and a group R^(d). A is morepreferably benzyl that bears 1 or 2 substituents which are selected fromnitro, halogen, a group R^(a), a group R^(b), a group R^(c) and a groupR^(d) and even more preferably benzyl that bears in the ortho positionnitro, a group R^(a), a group R^(b), a group R^(c) or group R^(d).

In the compounds of the formulae (I), (III), (V) and (VI) R⁴ ispreferably H, C₁-C₂ alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy,C₁-C₂-haloalkoxy, aryl, aryl-C₁-C₂-alkoxy, where the aryl groups in thetwo latter radicals optionally bear 1, 2 or 3 substituents which areselected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy. R⁴ is more preferably C₁-C₂-alkoxy, C₁-C₂-haloalkoxyor benzyloxy, where the phenyl group of the latter radical optionallybears 1, 2 or 3 substituents which are selected from halogen,C₁-C₂-alkyl, C₁-C₂-haloalkyl and C₁-C₂-alkoxy. R⁴ is even morepreferably methoxy, halomethoxy or benzyloxy.

In the compounds of the formulae (I), (III) and (VI) R⁵ is preferablyC₁-C₂-alkyl, C₁-C₂-haloalkyl or aryl-C₁-C₂-alkyl, where the aryl groupin the latter radical optionally bears 1, 2 or 3 substituents which areselected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy. R⁵ is more preferably C₁-C₂-alkyl or C₁-C₂-haloalkyland even more preferably methyl or halomethyl.

In the compounds of the formula (II) X is preferably iodine or bromineand more preferably bromine.

In the compounds of the formulae (Ia), (IIIa), (IV), (V) and (VI) p ispreferably 0, 1 or 2 and especially preferably 0 or 1. When p is 1, R³is preferably in the para or meta position to the attachment point ofthe methylene bridge.

In the compounds of the formulae (Ia), (IIIa), (IV), (V) and (VI) R³ ispreferably halogen, C₁-C₂ alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy orC₁-C₂-haloalkoxy. R³ is more preferably chlorine, fluorine, C₁-C₂-alkylor C₁-C₂-haloalkyl and even more preferably chlorine, fluorine, methylor halomethyl.

Examples of compounds of formula II are compounds of formula IIa

in which X has the general or preferred meaning given above.

Examples of compounds of the formula III are compounds of the formulaIIIa

in which

-   -   each R³ is independently selected from halogen, cyano,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;    -   p is 0, 1, 2 or 3;    -   Y is nitro, a group R^(a), a group R^(b), a group R^(c) or a        group R^(d); and    -   R², m, R^(a), R^(b), R^(c) and R^(d) are each as defined above.

The inventive conversions described hereinafter are performed inreaction vessels customary for such reactions, the reaction beingconfigurable in a continuous, semicontinuous or batchwise manner. Ingeneral, the particular reactions will be performed under atmosphericpressure. The reactions may, however, also be performed under reduced orelevated pressure.

The conversion in step (i) of the process according to the invention forpreparing substituted 1-phenylpyrazoles I is a cross-coupling reactionleading to the formation of a C—N bond. The reaction is effected bycontacting the starting compounds, i.e. an phenyl halide II and apyrazole derivative III, and also a base and a catalytic system,preferably in a solvent, under suitable reaction conditions.

In general, step (i) is performed under temperature control. Thereaction is typically effected in a closed or unclosed reaction vesselwith stirring and heating apparatus.

The reactants can in principle be contacted with one another in anydesired sequence. For example, the phenyl halide II, if appropriatedissolved in a solvent or in dispersed form, can be initially chargedand admixed with the pyrazole derivative III or, conversely, thepyrazole derivative III, if appropriate dissolved in a solvent or indispersed form, can be initially charged and admixed with the phenylhalide II. Alternatively, the two reactants can also be addedsimultaneously to the reaction vessel. The catalytic system and the basecan, independently of each other, be added before or after the additionof one of the reactants or else together with one of the reactants,either in a solvent or in bulk. As an alternative to their jointaddition the two components of the catalytic system, the ligand and themetal compound, can be added separately to the reaction vessel. Both ofthem can independently of one another be added before or after theaddition of one of the reactants or else together with one of thereactants.

It has been found to be appropriate to initially charge the reactionvessel with the phenyl halide II, the pyrazole derivative III, the baseand the metal compound and one or more ligands jointly. After exchangingthe atmosphere to nitrogen or argon, the solvent is added.

Suitable solvents depend in the individual case on the selection of theparticular reactants and reaction conditions. It has generally beenfound to be advantageous to use an aprotic organic solvent for thereaction of the compounds (II) with the compounds (III). Useful aproticorganic solvents here include, for example, aliphatic C₃-C₆-ethers, suchas 1,2-dimethoxyethane (DME), diethylene glycol dimethyl ether(diglyme), diethyl ether, dipropyl ether, methyl isobutyl ether,tert-butyl methyl ether and tert-butyl ethyl ether, aliphatichydrocarbons, such as pentane, hexane, heptane and octane, and alsopetroleum ether, cycloaliphatic hydrocarbons, such as cyclopentane andcyclohexane, alicyclic C₃-C₆-ethers, such as tetrahydrofuran (THF),tetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran and1,4-dioxane, aromatic hydrocarbons, such as benzene, toluene, thexylenes and mesitylene, short-chain ketones, such as acetone, ethylmethyl ketone and isobutyl methyl ketone, amides such asdimethylformamide (DMF), dimethylacetamide and N-methylpyrrolidone(NMP), dimethyl sulfoxide (DMSO), acetonitrile, or mixtures of thesesolvents with one another.

If the catalytic system includes a copper compound and in particular acopper(I) compound, the solvent for the conversion iri step (i) ispreferably selected from aliphatic C₃-C₆ ethers, alicyclic C₃-C₆-ethers,aromatic hydrocarbons and mixtures thereof, and more preferably fromDME, diglyme, THF, 1,4-dioxane, toluene and mixtures thereof. In thiscontext toluene, 1,4-dioxane and DME are particularly preferred solventsfor the conversion in step (i).

If the catalytic system includes an iron compound and in particular aniron(III) compound, the solvent for the conversion in step (i) ispreferably selected from aliphatic C₃-C₆-ethers, alicyclic C₃-C₆-ethers,aromatic hydrocarbons, amides, DMSO and mixtures thereof, and morepreferably from 1,4-dioxane, THF, toluene, NMP, DMF, DMSO and mixturesthereof. In this context DMF, DMSO, 1,4-dioxane and mixtures thereof areparticularly preferred solvents for the conversion in step (i).

If the catalytic system includes a palladium compound the solvent forthe conversion in step (i) is preferably selected from aliphaticC₃-C₆-ethers, alicyclic C₃-C₆-ethers, aromatic hydrocarbons, amides,DMSO and mixtures thereof, and more preferably from diethyl ether, THF,toluene, NMP, DMF, DMSO and mixtures thereof. In this context toluene isthe particularly preferred solvent for the conversion in step (i).

The total amount of the solvent used in step (i) of the processaccording to the invention is typically in the range from 200 to 5000 gand preferably in the range from 300 to 4000 g, based on 1 mol of thepyrazole derivative III.

Preference is given to using solvents which are essentially anhydrous,i.e. have a water content of less than 1000 ppm and especially not morethan 100 ppm.

In a preferred embodiment of the invention, in step (i), the phenylhalide of the formula II is used in an amount of 0.1 to 1.5 mol, morepreferably of 0.5 to 1.2 mol, even more preferably of 0.7 to 0.9 mol andespecially of 0.75 to 0.85 mol, based in each case on 1 mol of thepyrazole derivative of the formula III.

Pyrazole derivatives of the formula (III) can be prepared by customaryprocesses. In case the variable A is an optionally substituted benzylgroup, they are obtainable, for instance, by etherifying thecorresponding 3-hydroxypyrazole that may carry a temporary N-protectiongroup such as acetyl, with the corresponding benzyl bromide in thepresence of a base, as described, for example, in WO 96/01256 and WO99/06373. Suitable 3-hydroxypyrazoles can in turn be prepared forinstance by reacting hydrazine either with the corresponding propiolicacid ester, as described for example in EP 0680954 A2, or with thecorresponding (E)-methyl-3-methoxyacrylate, as described for example inG. A. Erler, W. Holzer, Molbank 2006, M464. The phenyl halides of theformula (II) are either commercially available or can be produced bystandard methods well known in the art.

For the conversion in step (i) of the process according to the inventionpreferably those pyrazole derivatives of the formula (III) are employedthat correspond to formula (IIIa)

in which

-   -   each R³ is independently selected from halogen, cyano,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,    -   p is 0, 1, 2 or 3,    -   Y is halogen, nitro, a group R^(a), a group R^(b), a group R^(c)        or a group R^(d), and    -   R², m, R^(a), R^(b), R^(c) and R^(d) are each as defined herein        before.

According to a preferred embodiment of the invention in step (i) those3-benzyloxypyrazoles IIIa are employed in which Y represents a bromine,nitro or a group R^(c) and the variables R², R³, m and p have themeanings mentioned herein as preferred.

According to a particularly preferred embodiment of the invention instep (i) those 3-benzyloxypyrazoles IIIa are employed in which Yrepresents nitro or a group R^(c), specifically nitro, and the variablesm and p both are 0.

It is suspected that the mechanism of the reaction in step (i)corresponds to the mechanism proposed for similar transition metalcatalyzed cross-coupling reactions. Accordingly, the first step of acatalytic cycle involves the oxidative addition of the metal compound ofthe catalytic system into the phenyl-halogen bond of compound (II) toform a metal ion intermediate, to which in the next step a nucleophilederived from compound (III) is transferred. The subsequent step is areductive elimination that yields the coupled product (I) andregenerates the active metal compound species. Alternatively, at leastif a catalytic system including a copper compound is used, the reactionmechanism may involve a similar catalytic cycle in which, however, theoxidation state of copper does not change. As a further possibility inthe first step of the catalytic cycle the copper compound of thecatalytic system may first interact with the nucleophile derived fromcompound (III) instead of with the phenyl halide II.

Suitable catalytic systems for the reaction of a compound II with acompound III in step (i) of the process according to the invention arepreferably selected from

a) palladium catalysts in which palladium has an oxidation state of 0 or2,

b) iron catalysts in which iron has an oxidation state 2 or 3, and

c) copper catalysts in which copper has an oxidation state 0, 1 or 2.

The catalytic system of the process of the invention can be employed inthe form of a preformed metal complex which comprises the metal compoundand one or more ligands. Alternatively, the catalytic system is formedin situ in the reaction mixture by combining a metal compound, hereinalso termed pre-catalyst, with one or more suitable ligands to form acatalytically active metal complex in the reaction mixture.

Suitable pre-catalysts are selected from neutral metal complexes, oxidesand salts of palladium, iron or copper. Useful palladium(II) salts forthis purpose are, for example, bis[dibenzylideneacetone]palladium(0),tris[dibenzylideneacetone]dipalladium(0), palladium(II) chloride,bis(acetonitrile)palladium(II) chloride and palladium(II) acetate, ofwhich bis[dibenzylideneacetone]palladium(0),tris[dibenzylideneacetone]dipalladium(0) are preferred. Useful iron(III)pre-catalysts are iron(III) chloride, iron(III) acetylacetonate andiron(III) oxide. Useful copper(I) pre-catalysts are copper(I) chloride,copper(I) bromide, copper(I) iodide, copper(I) thiophene-2-carboxylateand copper(I) oxide.

Suitable ligands of the catalytic system for the conversion in step (i)of the process according to the invention are, for example, mono- orbidentate phosphines of the formulae VII and VIII shown below

in which R⁶ to R¹² are each independently C₁-C₈-alkyl, C₅-C₈-cycloalkyl,adamantyl, aryl-C₁-C₂-alkyl, ferrocenyl or aryl which is optionallysubstituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, fluorine or chlorine, and T isferrocenediyl or a linear C₂-C₅-alkanediyl which is optionallysubstituted by C₁-C₈-alkyl or C₃-C₆-cycloalkyl and is optionally part ofone or two mono- or bicyclic rings which are unsubstituted orsubstituted.

More particularly, Tin the compound of the formula VIII isC₂-C₄-alkylene, C₀-C₁-alkyleneferrocenyl, 1,2′-biphenyl-2,2′-diylor1,1-binaphthyl-2,2′-diyl, where the latter four groups may optionally besubstituted by C₁-C₈-alkyl or C₁-C₄-alkoxy, and where C₂-C₄-alkylene mayadditionally have one or more substituents selected fromC₃-C₇-cycloalkyl, aryl and benzyl. In this connection, 1 to 4 carbonatoms of the C₂-C₄-alkylene may be part of a C₃-C₇-cycloalkyl ring. Arylhere is naphthyl or optionally substituted phenyl. Aryl is preferablyphenyl or tolyl, more preferably phenyl. C₀-C₁-Alkyleneferrocenyl isespecially ferrocenediyl, where each one of the two phosphorus atoms isbonded to a different cyclopentadiene moiety of the ferrocene, ormethylene-ferrocenyl, where one of the phosphorus atoms is bonded viathe methylene group to a cyclopentadiene, the second phosphorus atom isbonded to the same cyclopentadiene, and the methylene group mayoptionally have 1 or 2 further substituents selected from

Monodentate complex ligands of the formula VII preferred herein arethose in which R⁶, R⁷ and R⁸ are each optionally substituted phenyl, forexample triphenylphosphine (TPP), and those in which R⁶, R⁷ and R⁸ areeach C₁-C₆-alkyl, C₅-C₈-cycloalkyl, adamantyl, or optionally substitutedbiphenyl, for example di-1-adamantyl-n-butylphosphine,tri-tert-butylphosphine (TtBP), methyldl-tert-butylphosphine,tricyclo-hexylphosphine, 2-(dicyclohexylphosphino)biphenyl and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(X-Phos). Inaddition, it is also possible to use phosphites, for exampletris(2,4-di-tert-butylphenyl)phosphite (cf. A. Zapf et al., Chem. Eur.J. 2000, 6, 1830).

Bidentate complex ligands of the formula VIII preferred herein are thosethat correspond to the formula IX:

in which R⁹ to R¹² are each as defined above and are preferably eachindependently phenyl which optionally bears one to three substituentsselected from methyl, methoxy, fluorine and chlorine. R¹³ and R¹⁴ areeach independently hydrogen, C₁-C₈-alkyl or C₃-C₆-cycloalkyl, or R¹³ andR¹⁴ form, together with the carbon atom to which they are bonded, a 3-to 8-membered ring which is optionally substituted by C₁-C₆-alkyl. R¹³and R¹⁴ are preferably each independently selected from methyl, ethyl,1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

Examples of preferred compounds of the formula (IX) are1,3-bis(diphenylphosphinyl)-2-methylpropane,1,3-bis(diphenylphosphinyl)-2,2-dimethylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-ethylpropane,1,3-bis(diphenylphosphinyl)-2,2-diethylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-propylpropane,1,3-bis(diphenylphosphinyl)-2-ethyl-2-propylpropane,1,3-bis(diphenylphosphinyl)-2,2-dipropylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-butylpropane,1,3-bis(diphenylphosphinyl)-2-ethyl-2-butylpropane,1,3-bis(diphenylphosphinyl)-2-propyl-2-butylpropane,1,3-bis(diphenylphosphinyl)-2,2-dibutylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-cyclopropylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-cyclobutylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-cyclopentylpropane,1,3-bis(diphenylphosphinyl)-2-methyl-2-cyclohexylpropane, morepreferably 1,3-bis(diphenylphosphinyl)-2,2-dimethylpropane and1,3-bis(diphenylphosphinyl)-2-ethyl-2-butylpropane.

Preferred ligands of the catalytic system for the conversion in step (i)of the process according to the invention are the bidentate ligands offormula X

in which

V and W are independently selected from nitrogen, that optionally may belinked to a hydrogen atom, oxygen and sulfur, where nitrogen isincorporated as part of an amine, an imine or a nitrogen containingheterocycle, where oxygen is incorporated as an oxo substituent, as partof a hydroxy group, an alkoxy group or an oxygen containing heterocycleand where sulfur is incorporated as part of a thioketone group, a thiolgroup (—SH), an alkylthio group or a sulfur containing heterocycle;

T′ is either absent or a methandiyl (—CH₂—) or a methendiyl (═CH—)bridge;

R¹⁵ and R¹⁶, independently from one another, are either absent orselected from hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl or aryl, where thelatter three radicals may optionally carry 1, 2 or 3 substituentsselected from halogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; or

if V and/or W are nitrogen, the respective radical R¹⁵ and/or R¹⁶ bondedthereto may be hydroxy or C₁-C₄-alkoxy;

R¹⁷ and R¹⁸ are independently selected from hydrogen, hydroxy,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl or aryl, where the latter fourradicals may optionally carry 1, 2 or 3 substituents selected fromhalogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; or

one or more pairs of moieties selected from T′, R¹⁵, R¹⁶, R¹⁷, and R¹⁸together with the atoms to which they are bound, form a 3-, 4-, 5-, 6-or 7-membered saturated, unsaturated or aromatic carbocyclic ring or a3-, 4-, 5-, 6- or 7-membered saturated, unsaturated or aromaticheterocyclic ring containing 1, 2, or 3 heteroatoms selected from O, Sand N as ring members, where the carbocyclic or heterocyclic ring mayoptionally carry 1, 2 or 3 substituents selected from halogen,C₁-C₄-alkyl and C₁-C₄-haloalkyl; and

is a single or double bond.

Preferred ligands of the formula X are selected from 1,2-diols, such asethan-1,2-diol, 1,2-diamines, such as 1,2-diaminoethane,N,N′-dimethyl-1,2-diaminoethane, 1,2-diaminocyclohexane, e.g.trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,2-diaminocyclohexane, e.g.trans-N,N′-dimethyl-1,2-diaminocyclohexane of formula XI (see below),1,2-aminoalcohols, such as N-methyl-2-aminoethanol, 1,2- and1,3-diketones, such as acetylacetone, hydroxylimines, such as thecompounds of formulae XII and XIII below, cyclic carboxylic acids havingusually 5, 6, 7 or 8 ring members, wherein the cycle contains besidescarbon atoms one or two heteroatom(s) selected independently from S, Oand N as ring members, and wherein a ring heteroatom is adjacent to thering carbon atom that carries the carboxyl group such as L-proline andthiophene-2-carboxylic acid, polycyclic heteroaromatic compounds, suchas 1,10-phenanthroline, heteroaromatic compounds, wherein two monocyclicheteroaromatic rings are linked via a single bond such as2,2′-bipyridine, and diimines, such asN,N′-bis(2,6-diisopropylphenyl)ethandiimine, and wherein 2,2′-Bipyridineand 1,10-phenanthroline may be unsubstituted or substituted, in the caseof the 1,10-phenanthroline preferably in the positions 4 and/or 7, with1, 2, 3 or 4 substituents selected from C₁-C₄-alkyl, C₃-C₇-cycloalkyl,phenyl, phenoxy and phenylthio, where the phenyl ring in the last 3radicals mentioned may carry 1, 2 or 3 substituents selected fromhalogen, C₁-C₄-haloalkyl and C₁-C₄-alkoxy.

Furthermore, suitable catalytic systems for the conversion in step (i)of the process according to the invention are also those that compriseat least one N-heterocydlic carbene, known as NHC ligands. These are,more particularly, reactive complex ligands, which are described, forexample, in G. A. Grasa et al., Organometallics 2002, 21, 2866. NHCligands can be obtained in situ from imidazolium salts, for example1,3bis(2,6-diisopropylphenyl)-4,5-H2-imidazolium chloride, with bases,and be converted to suitable catalysts in the presence of metalcompounds such as palladium(0) compounds, especially those of thetris(dibenzylideneacetone)dipalladium(0) orbis-(dibenzylideneacetone)palladium(0) type, or palladium, copper andiron salts such as palladium(II) acetate, copper(II) triflate andiron(II) chloride. However, it is also possible to prepare NHC complexsalts of metal compounds, e.g.(1,3-bis(2,6-diisopropylphenypimidazol-2-ylidene)(3-chloropyridyl)-palladium(II)dichloride, before-hand and to isolate them, and then to use them aspreformed catalysts in the inventive cross-couplings (cf. S. P. Nolan,Org. Lett. 2005, 7, 1829 and M. G. Organ, Chem. Eur. J. 2006, 12, 4749).

For the inventive reactions, the NHC ligands used are preferablysterically hindered imidazol-2-ylidene compounds, especially those ofthe formula XIV which bear bulky R¹⁹ and R²⁰ substituents in positions 1and 3 of the imidazole ring. Preferably, R¹⁹ and R²⁰ here are eachindependently aryl or hetaryl, each of which is unsubstituted or bears1, 2, 3 or 4 substituents, where the substituents are preferablyselected from C₁-C₈-alkyl and C₃-C₇-cycloalkyl. Particularly preferredR¹⁹ and R²⁰ substituents are phenyl radicals which bear, in positions 2and 6, preferably branched C₁-C₆-alkyl radicals.

Said catalytic systems of the invention that comprise a NHC ligand, inparticular those that are based on a palladium compound, may also bearat least one co-ligand. Such co-ligands are, for example, selected fromhetaryl with at least one nitrogen atom in the ring, especially pyridylwhich is unsubstituted or bears 1, 2 or 3 substituents selected fromhalogen, C₁-C₆-alkyl and C₁-C₈-alkoxy. A specific example of such aco-ligand is 3-chloropyridyl.

If the catalytic system comprises a palladium compound, then one or moreligands of the catalytic system for the conversion in step (i) arepreferably selected from the monodentate phosphines of formula VII, thebidentate phosphines of formula VIII and the NHC ligands of formula XIV,and particularly preferably from those mentioned herein as preferred. Inthis context even more preferred ligands are methyldi-tert-butylphosphine, tri-tert-butylphosphine and X-Phos.

If the catalytic system comprises an iron compound, then one or moreligands of the catalytic system for the conversion in step (i) aretypically selected from bidentate ligands, which are preferably ligandsof formula X, in particular those mentioned herein as preferred. In thiscontext preference is also given to ligands selected from 1,2-diamines,1,3-diketones and cyclic carboxylic acids having usually 5, 6, 7 or 8ring members, wherein the cycle contains besides carbon atoms one or twoheteroatom(s) selected independently from S, O and N as ring members,and wherein a ring heteroatom is adjacent to the ring carbon atom thatcarries the carboxyl group, in particular those of these ligands thatare of the formula X, such as specificallyN,N′-dimethyl-1,2-diaminoethane, acetylacetone and L-proline.

If the catalytic system comprises a copper compound, then one or moreligands of the catalytic system for the conversion in step (i) aretypically selected from bidentate ligands, which are preferably ligandsof formula X, in particular those mentioned herein as preferred. In thiscontext preference is also given to ligands selected from 1,2-diamines,hydroxylimines and cyclic carboxylic acids having usually 5, 6, 7 or 8ring members, wherein the cycle contains besides carbon atoms one or twoheteroatom(s) selected independently from S, 0 and N as ring members,and wherein a ring heteroatom is adjacent to the ring carbon atom thatcarries the carboxyl group, in particular those of these ligands thatare of the formula X. More preference is given to 1,2-diamines of theformula X. Examples of suitable ligands in this regard are L-proline,thiophene-2-carboxylic acid and the compounds of the formulae XI, XIIand XIII and in particular the compound of formula XI.

According to a preferred embodiment of the invention the catalyticsystem of the process of the invention comprises a copper compound andone or more, in particular one, ligand selected from ligands of formulaX, in particular those that are mentioned herein as being preferablyused in combination with a copper compound.

According to another preferred embodiment of the invention the one ormore ligands, in particular one ligand, and the metal compound, inparticular a copper compound, as pre-catalyst are charged separately tothe reaction vessel and the catalytic system used in the process of theinvention is formed thereafter. Preferably, the molar ratio of metalcompound to ligand is in the range of 1:2 to 1:20, more preferably inthe range of 1:5 to 1:15 and specifically 1:8 to 1:11. For example, itmay be particularly advantageous to use 8 to 10 molar equivalents ofcomplex ligand, based on one equivalent of the metal compound.

The metal compound of the catalytic system is used in the processaccording to the invention preferably in an amount of 0.1 to 15.0 mol %,preferably of 1.0 to 10.0 mol %, and especially of 3.0 to 7.0 mol %,based on the amount of the pyrazole derivative III used.

The reaction temperature of step (i) is determined by several factors,for example the reactivity of the reactants used and the type of thecatalytic system selected, and can be determined by the person skilledin the art in the individual case, for example by simple preliminarytests. In general, the conversion in step (i) of the process accordingto the invention is performed at a temperature in the range from 0 to250° C., preferably in the range from 20 to 200° C., more preferably inthe range from 50 to 150° C. and specifically in the range from 70 to120° C. Depending on the solvent used, the reaction temperature and onwhether the reaction vessel possesses a vent, a pressure of generally 1to 6 bar and preferably of 1 to 4 bar is established during thereaction.

The choice of base to be employed for the conversion in step (i) of theprocess of the invention depends on several factors, such as thereactivity of the reactants used and the type of the catalytic systemselected, and can be determined by the person skilled in the art in theindividual case, for example by simple preliminary tests. In general thebase is selected from bases commonly known to be useful for similarreactions, such as tri-alkali metal phosphates, e.g. trisodium phosphateand tripotassium phosphate, alkali metal alkanolates, e.g. potassiumisopropylate and sodium tert-butylate, and from alkali metal carbonates,e.g. sodium carbonate, potassium carbonate and rubidium carbonate. Inthis context preferred bases are tripotassium phosphate, sodiumtert-butylate, rubidium carbonate and potassium carbonate.

In the process according to the invention the base is preferably used inan amount of 0.1 to 5 mol, more preferably of 0.1 to 3 mol, even morepreferably of 0.2 to 2 mol and specifically of 0.3 to 1.7 mol, based ineach case on 1 mol of the pyrazole derivative of the formula (III).

According to a preferred embodiment of the invention, in step (i), thephenyl halide of the formula II is used in an amount of 0.7 to 0.9 moland the base is used in an amount of 0.2 to 2 mol, based in each case on1 mol of the pyrazole derivative of the formula III, and, in addition,the complex ligand is used in an amount of 8 to 11 mol based on 1 mol ofthe metal compound.

According to a particular preferred embodiment of the invention, in step(i), the phenyl halide of the formula II is used in an amount of 0.75 to0.85 mol and the base is used in an amount of 0.3 to 1.7 mol, based ineach case on 1 mol of the pyrazole derivative of the formula III, and,in addition, the complex ligand is used in an amount of 8 to 10 molbased on 1 mol of the metal compound.

The present invention further provides a process for preparing acompound of the formula (IV),

in which

R¹, n, R², m, R³ and p are each as defined herein before,

comprising.

-   -   (i) providing a 1-phenylpyrazole of formula (Ia) by reacting a        phenyl halide of the formula (II) with a 3-benzyloxypyrazole        IIIa, in which Y is nitro, according to the process described        above,        and further,

-   -   (ii) converting the 1-phenylpyrazole of the formula Ia to a        N-phenylhydroxylamine IV.

Conversion into the 1-phenylpyrazole of the formula IV may beaccomplished by hydrogenation which can be performed according to knownmethods for hydrogenating aromatic nitro compounds, e.g. byelectrochemical reduction, by reduction with metals, such as zinc dustor amalgams, or, preferably, by catalytic hydrogenation as described forexample in WO 96/22967 and WO 99/12911.

In case a catalytic hydrogenation process is used for the conversion instep (ii) of the inventive process the reaction is preferably performedin the presence of a commercial catalyst, such as platinum or palladiumon a carrier, or Raney nickel or Raney cobalt. If a platinum or apalladium catalyst is to be used, it may have to be doped with sulfur orselenium in order to obtain sufficient selectivity, since the startingmaterial, compound Ia, contains sensitive groups, such as a benzyl ethergroup and possibly halogens.

The conversion in step (ii) is preferably carried out by catalytichydrogenation using a platinum or a palladium catalyst which in generalcontains platinum or palladium on a carrier material, such as carbon,graphite, barium sulphate or silicon carbide. The platinum or apalladium content of the catalyst is not critical and can be varied inwide limits.

A content of from 0.1 to 15% by weight, preferably from 0.5 to 10% byweight, based on the carrier material carbon is expedient. In relationto the compound Ia the amount of the platinum or palladium employed isin general from 0.001 to 1% by weight, preferably from 0.01 to 0.1% byweight.

Said catalytic hydrogenation using a platinum or a palladium catalyst isusually carried out in the presence of a base, which is preferably anamine, e.g. an aromatic amine such as pyridine, a heterocyclic aminesuch as piperidine or N-alkylmorpholine, or primary, secondary ortertiary aliphatic amines, such as triethylamine, diethylamine andn-propylamine. Preferably the hydrogenation is carried out in thepresence of a primary C₁-C₄ alkylamine, such as n-propylamine,isopropylamine, n-butylamine or tert-butylamine, with n-propylaminebeing particularly preferred.

The aforementioned amines, in particular the N-alkylmorpholines, mayalso act as solvent of the hydrogenation reaction. Preference is given,however, to carrying out the hydrogenation in a mixture of an inertaprotic solvent with an amine, in particular an amine selected fromthose mentioned above as preferred. Suitable inert aprotic solvents aree.g. aliphatic or alicyclic ethers, such as THF or aliphatic or aromatichydrocarbons, such as benzene, toluene or chlorobenzene. Preferred inertaprotic solvents are aromatic hydrocarbons, in particular toluene.

For said catalytic hydrogenation in step (ii) the amine is used, as arule, in a concentration of from 1 to 20% by weight, preferably from 5to 17% by weight, based on the solvent. Higher concentrations arepossible but usually result in scarcely any improvements in the yieldand selectivity and are therefore uneconomical. In relation to thecompound Ia to be hydrated the amine is typically used in a molar ratioof from 1 to 15, preferably in a molar ratio of from 2 to 12.

The chosen temperature range for the catalytic hydrogenation is from−20° C. to +30° C., preferably from −5 to +10° C. The minimumtemperature is determined only by the freezing point of the solventused. The maximum temperature is dependent on the compound Ia to behydrogenated and on the reaction parameters. To avoidoverhydro-genation, a pressure which is from atmospheric pressure to 10bar gauge pressure is established at the temperature at which thehydrogenation usually takes place sufficiently rapidly. In general, thehydrogen gas is introduced into the hydrogenation reactor at atmosphericor slightly superatmospheric pressure.

The starting materials need not be present in dissolved form forcarrying out the novel process. The reaction usually gives optimumresults even in suspension.

After the end of the reaction, a major part of the added amine isremoved by distilling it off and/or by extraction with water. Thedistillation is preferably carried out under nitrogen or at reducedpressure. In the case of sensitive hydroxylamines IV complete absence ofoxygen may be required.

Since the handling of the generally oxygen-sensitive hydroxylamines isdifficult in some cases, it may be advantageous to process thehydroxylamines IV further immediately after removal of the aliphaticamine by extraction or distillation. In the removal of the amine bydistillation, it is advantageous if the amine has a lower boiling pointthan the solvent. In this way a solution of the hydroxylamine in thesolvent is obtained and can be further processed immediately, forinstance in step (iii) of the process of the invention.

The present invention further provides a process for preparing acompound of the formula (V)

in which

R¹, n, R², m, R³, p and R⁴ are each as defined herein before, comprising

(i) providing a 1-phenylpyrazole of formula (Ia) by reacting a phenylhalide of the formula (II) with a 3-benzyloxypyrazole IIIa, in which Yis nitro, according to the process described above, followed by

(ii) converting the 1-phenylpyrazole of the formula Ia to aN-hydroxylamine of the formula IV and, further

(iii) converting the compound of the formula IV into a compound of theformula V.

Conversion into a compound of the formula V involves N-acylation of thecompound of the formula IV. The N-acylation of compound IV in step (iii)can be performed according to known methods for acylating aromatichydroxylamines, e.g. those described in WO 96/01256 and WO 99/12911.

The hydroxylamine of the formula IV produced in step (ii) is preferablywithout further purification directly introduced into step (iii) ascrude product that is obtained after removal of the amine bydistillation or extraction.

The N-acylation in step (iii) is generally carried out by reacting ahydroxylamine of the formula IV with a reagent of the formula (XV)

in which R⁴ is as defined herein before and L¹ is a leaving group thatis typically hydroxyl, halide, especially chloride or bromide, an —OR²¹radical or an —O—CO—R²² radical, where the definitions of the R²¹ andR²² substituents are explained hereinafter.

When the reagent XV is used with L¹ being a hydroxyl group (R⁴—COOH),the reaction can be performed in the presence of a coupling reagent.Suitable coupling reagents (activators) are known to those skilled inthe art and are selected, for example, from carbodiimides such as DCC(dicyclohexylcarbodiimide) and DCl (diisopropylcarbo-diimide),benzotriazole derivatives such as HBTU((O-benzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate)and HCTU(1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate),and phosphonium activators such as BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)tripyrrolidinephosphonium hexafluorophosphate)and Py-BrOP (bromotripyrrolidinephosphonium hexafluorophosphate). Ingeneral, the activator is used in excess. The benzotriazole andphosphonium coupling reagents are generally used in a basic medium.

Suitable acylating reagents XV are also derivatives of compounds R⁴—COOHthat can react with the hydroxylamine IV to give the hydroxylamide V,for example esters R⁴—C(O)—OR²¹ (L¹=OR²¹), acid halides R⁴—C(O)X inwhich X is a halogen atom (L¹=halogen), or acid anhydridesR⁴—C(O)—O—(O)C—R²² (L¹=—O—C(O)—R²²).

The acid anhydride R⁴—C(O)—O—(O)C—R²² is either a symmetric anhydrideR⁴—C(O)—O—(O)C—R⁴ or an asymmetric anhydride, in which —O—(O)C—R²² is agroup which can be displaced readily by the hydroxylamine IV used in thereaction. Suitable acid derivatives which can form suitable mixedanhydrides with the compound R⁴—COOH are, for example, the esters ofchloroformic acid, e.g. isopropyl chloroformate and isobutylchloroformate, or of chloroacetic acid.

Suitable esters R⁴—COOR²¹ derive preferably from alkanols R²¹—OH inwhich R²¹ is C₁-C₄-alkyl, such as methanol, ethanol, propanol,isopropanol, n-butanol, butan-2-ol, iso-butanol and tert-butanol,preference being given to the methyl and ethyl esters (R²¹=methyl orethyl). Suitable esters may also derive from C₂-C₆-polyols, such asglycol, glycerol, trimethylolpropane, erythritol, pentaerythritol andsorbitol, preference being given to the glyceryl ester. When polyolesters are used, it is possible to use mixed esters, i.e. esters withdifferent R²¹ radicals.

Alternatively, the ester R⁴—COOR²¹ is a so-called activated ester, whichis obtained in a formal sense by the reaction of compound R⁴—COOH withan activated ester-forming alcohol, such as p-nitrophenol,N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide or OPfp(pentafluorophenol).

Alternatively, the reagent XV used for the N-acylation in step (iii) maypossess another conventional leaving group L¹, for example pyrrolyl orimidazolyl.

The inventive N-acylations with the above-described reagents of theformula XV can be performed analogously to known processes.

Preference is given to using, for the N-acylation of compounds of theformula IV, carbonyl halides of the formula (XV), especially those inwhich the leaving group L¹ is chlorine or bromine, and in particular ischlorine. To this end, preferably 0.5 to 2 mol and especially 0.8 to 1.7mol of the carbonyl chloride XV are used per 1 mol of the compound IV.

The acylation is advantageously carried out in the presence of an inertorganic solvent which was used in the hydrogenation in previous step(ii), for example in an aprotic solvent, such as an aliphatic oraromatic hydrocarbon, e.g. toluene, xylene, heptane or cyclohexane, orin an aliphatic or cyclic ether, preferably DME, THF or dioxane. It isalso possible to add a polar aprotic solvent, such as an aliphaticketone, preferably acetone, an amide, preferably DMF, or a sulfoxide,preferably DMSO, ureas, e.g. tetramethylurea or1,3-dimethyltetrahydro-2(1H)-pyrimidinone, a carboxylic ester, such asethyl acetate, or a halogenated aliphatic or aromatic hydrocarbon, suchas dichloromethane or chlorobenzene, to the reaction mixture.

As a rule, the reaction is carried out in the presence of an inorganicbase, such as sodium hydroxide, potassium hydroxide, sodium carbonate,sodium bicarbonate, potassium carbonate or potassium bicarbonate, anamine, such as triethylamine, pyridine or N,N-diethylaniline, or analkali metal alcoholate, e.g. sodium methylate or ethylate or potassiumtert-butylate. However, the base is not absolutely essential and can beomitted or may, if required, be replaced by other acid acceptors, forexample basic ion exchangers or water.

The reaction can also be carried out in a biphasic system consisting ofan aqueous phase, that may or may not contain a base, such as alkalimetal or alkaline earth metal hydroxides or carbonates, and a secondphase that is based on at least one essentially water-immiscible organicsolvent. Suitable phase-transfer catalysts that may be present in thereaction medium are, for example, ammonium halides andtetrafluoroborates and phosphonium halides.

The reaction temperature of the acylation is in general from −30° C. tothe reflux temperature of the solvent used, preferably from −20 to 50°C.

The workup of the reaction mixtures obtained via the N-acylationreaction in step (iii) and the isolation of the compound of the formula(V) are effected in a customary manner, for example by filtering off theprecipitated reaction product V, by an aqueous extractive workup, byremoving the solvent, for example under reduced pressure, or by acombination of these measures. Further purification can be effected, forexample, by crystallization, distillation or chromatography.

The present invention further provides a process for preparing acompound of the formula (VI)

in which

R¹, n, R², m, R³, p, R⁴ and R⁵ are each as defined herein before,

comprising

(i) providing a 1-phenylpyrazole of formula (Ia) by reacting a phenylhalide of the formula (II) with a 3-benzyloxypyrazole IIIa, in which Yis nitro, according to the process described above, followed by

(ii) converting the 1-phenylpyrazole of the formula Ia to aN-hydroxylamine of the formula IV,

(iii) converting the compound of the formula IV into a compound of theformula V and, further,

(iv) converting the compound of the formula V into a compound of theformula VI.

Conversion into a compound of the formula VI involves 0-alkylation tothe corresponding compound V. The O-alkylation of N-hydroxylamide V instep (iv) can be performed according to known methods for O-alkylatingaromatic N-hydroxylamides, e.g. those described in WO 96/01256 and WO99/12911.

The O-alkylation in step (iv) is generally carried out by reacting acompound V with a reagent of the formula (XVI)R⁵-L²  (XVI)in which R⁵ is as defined herein before and L² is a leaving group thatis typically a halide, especially chloride or bromide, a sulfate, asulfonate, preferably a methanesulfonate (mesylate), benzenesulfonate,o-toluenesulfonate (tosylate), p-bromobenzene-sulfonate (brosylate) ortrifluoromethanesulfonate (triflate), or a diazo group.

Preferred reagents XVI are the halides and, in case R⁵ is methyl,dimethyl sulfate.

The alkylation in step (iv) of the inventive process is usually carriedout in an inert solvent or diluent, preferably in the presence of abase.

Examples of suitable solvents or diluents are those mentioned withrespect to the N-acylation in step (iii) described above.

Suitable bases are inorganic bases, for example carbonates, such aspotassium carbonate or sodium carbonate, bicarbonates, such as potassiumbicarbonate or sodium bicarbonate, hydroxides, such as sodium hydroxideor potassium hydroxide, alkali metal hydrides, for example sodiumhydride or potassium hydride, organic bases, such as amines, eg.triethylamine, pyridine or N,N-diethyl-aniline, and alkali metalalcoholates, such as sodium methylate or ethylate or potassiumtert-butylate.

Preferably, the reagent XVI (for example dimethyl sulfate) and theN-acylated hydroxylamine V are initially taken and the base (for examplepotassium hydroxide) is metered in.

The amount of base or reagent XVI is preferably from half the molaramount to twice the molar amount, based on the amount of the compound V.Base and reagent XVI are particularly preferably used in a slightexcess.

In general, the reaction temperature in the alkylation is from −78° C.to the boiling point of the reaction mixture, preferably from −30 to100° C. and particularly preferably from 10 to 90° C.

As in the case of the N-acylation in step (iii), the O-alkylation, too,can be carried out in a biphasic system. The abovementionedphase-transfer catalysts may be used.

The workup of the reaction mixtures obtained via the O-alkylationreaction in step (iv) and the isolation of the compound of the formulaVI are effected in a customary manner, for example by measures mentionedbefore regarding the N-acylation product V from step (iii).

The processes of the invention that include step (i) allow preparation,with a low level of complexity and in good yields and selectivities, of1-phenylhalides I which are suitable starting compounds for preparingthe N-hydroxylamines IV, N-hydroxylamides V and N-alkoxyamides VIobtainable therefrom according to processes of the invention includingsteps (ii), (iii) and (iv), respectively.

In a further aspect the invention relates to the 3-benzyloxypyrazoles ofthe formula (IIIa)

in which

Y is nitro, a group R^(a), a group R^(b), a group R^(c) or a groupR^(d),

each R² is independently selected from cyano, nitro, halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio and C₁-C₄-alkoxycarbonyl;

m is 0, 1 or 2;

-   -   each R³ is independently selected from halogen, cyano,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, and    -   p is 0, 1, 2 or 3.

Preference is given to compounds IIIa in which the variables Y, R², m,R³ and p have the aforementioned preferred meanings.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES I. Preparation of the 3-benzyloxypyrazoles of the formula(IIIa) I.3-Hydroxy-1H-pyrazole

Hydrazin hydrate (80% in H₂O, 6.7 mL, 110 mmol) was slowly added to asolution of (E)-methyl methoxyacrylate (11.6 g, 100 mmol) in 10 mL ofmethanol. The solution was heated to reflux for 90 min upon completeaddition. Then, all volatiles were removed under reduced pressure togive the product as a slightly yellow solid (8.2 g, 97.5 mmol, 98%yield) that was sufficiently pure for further transformations.

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)=10.40 (bs, 1H); 7.35 (d, J=3.0 Hz,1H); 5.44 (d, J=3.0 Hz, 1H).

¹³C NMR (DMSO-d₆, 125 MHz): δ (ppm)=161.0; 130.1; 89.3.

Melting point: 137° C.

I.2 1-Acetyl-3-hydroxy-1H-pyrazole

A solution of 3-hydroxy-1H-pyrazole (8.2 g, 97.5 mmol) in pyridine (40mL) was heated to 95° C. A mixture consisting of acetic anhydride (9.4mL, 102 mmol) and pyridine (20 mL) was added over 15 min; then stirringat 95° C. was continued for 60 min. All volatiles were then removedunder reduced pressure and to the residue was added 200 mL of diethylether. The slurry was stirred overnight at room temperature, then thesolid was filtered off and rinsed with diethyl ether. The product wasobtained as an off-white solid (10.3 g, 81.7 mmol, 84% yield).

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)=10.95 (s, 1H); 8.13 (d, J=3.0 Hz,1H); 6.00 (d, J=3.0 Hz, 1H), 2.48 (s, 3H).

¹³C NMR (DMSO-d₆, 125 MHz): δ (ppm)=167.9; 163.9; 129.8; 99.8; 21.3.

Melting point: 191° C.

I.3 3-(2-Nitrobenzyloxy)-1H-pyrazole

A suspension of 1-acetyl-3-hydroxy-pyrazole (3.4 g, 27.0 mmol),2-nitrobenzyl bromide (5.9 g, 27.3 mmol) and K₂CO₃ (4.0 g, 28.9 mmol) in75 mL of 2-butanone was heated to reflux for 90 min. After cooling toroom temperature, the precipitated salts were filtered off and rinsedwith tert-butyl methyl ether (TBME). The filtrate was then concentratedunder reduced pressure (50 mbar) and redissolved in a mixture oftetrahydrofuran (THF) and methanol (MeOH) (3:2, 50 mL). 2 mL of a 10%NaOH solution were added and the solution was stirred 60 min at ambienttemperature. Then, all volatiles were removed under reduced pressure (50mL). The residue was diluted with 20 mL of H₂O and 30 mL of ethylacetate (EtOAc). The aqueous phase was extracted with EtOAc (2×20 mL).The combined org. layers were washed with water and brine (both 30 mL)and dried over Na2SO₄. The crude product was obtained after evaporationof all volatiles and recrystallised from dichloromethane (15 mL) to givethe product as yellowish crystals (5.0 g, 22.8 mmol, 84%).

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)=11.93 (s, 1H); 8.10 (d, J=8.0 Hz,1H); 7.77-7.80 (m, 2H); 7.58-7.62 (m, 1H); 7.54 (d, J=2.5 Hz, 1H); 5.74(d, J=2.5 Hz, 1H); 5.59 (s, 2H).

¹³C NMR (DMSO-d₆, 125 MHz): δ (ppm)=162.3; 147.3; 133.8; 133.1; 130.1;129.0; 128.8; 124.5; 89.4; 66.6.

Melting point: 87° C.

I.4 3-(2-Bromobenzyloxy)-1H-pyrazole

A suspension of 1-acetyl-3-hydroxy-pyrazole (1.0 g, 7.9 mmol),2-bromobenzyl bromide (2.0 g, 7.9 mmol) and K₂CO₃ (1.2 g, 8.4 mmol) in20 mL of 2-butanone was heated to reflux for 90 min. After cooling toroom temperature, the precipitated salts were filtered off and rinsedwith tert-butyl methyl ether (TBME). The filtrate was then concentratedunder reduced pressure (50 mbar) and redissolved in a mixture oftetrahydrofuran (THF) and methanol (MeOH) (3:2, 25 mL). 1 mL of a 10%NaOH solution was added and the solution was stirred 60 min at ambienttemperature. Then, all volatiles were removed under reduced pressure (50mL). The residue was diluted with 10 mL of H₂O and 20 mL of ethylacetate (EtOAc). The aqueous phase was extracted with EtOAc (2×10 mL).The combined organic layers were washed with water and brine (both 20mL) and dried over Na₂SO₄. The crude product was obtained afterevaporation of all volatiles and used in the next step without furtherpurification (1.9 g, 7.5 mmol, 95%).

¹H NMR (CDCl₃, 500 MHz): δ (ppm)=7.56 (d, J=8.0 Hz, 2H); 7.36 (d, J=1.5Hz, 1H); 7.30 (t, J=7.5 Hz, 1H); 7.17 (dt, J=1.5 Hz, J=8.0 Hz, 1H); 5.80(d, J=2.5 Hz, 1H); 5.30 (s, 2H).

¹³C NMR (CDCl₃, 125 MHz): δ (ppm)=163.4; 136.5; 132.6; 130.3; 129.2;129.1; 127.5; 122.5; 90.8; 70.4.

I.5 Methyl N-{2-[3′-(1H-pyrazol)-yloxymethyl]-phenyl}-N-methoxycarbamate

A suspension of 1-acetyl-3-hydroxy-pyrazole (0.6 g, 5.1 mmol), methylN-(2-bromomethylphenyl)-N-methoxycarbamate (˜70% purity, 2.0 g, 5.1mmol) and K₂CO₃ (0.9 g, 6.6 mmol) in 20 mL of 2-butanone was heated toreflux for 90 min. The mixture was then cooled to room temperature andfiltered. The filtrate was concentrated and subjected to columnchromatography (SiO₂, hexane/ethyl acetate =100:0 to 80:20) to give theproduct as a tan liquid (0.9 g, 3.3 mmol, 65% yield). The acetylatedcompound (0.73 g, 2.3 mmol) was dissolved in 7 mL of methanol. 60 μL oftriethyl amine were added and the solution was stirred for 60 min atroom temperature. Then, all volatiles were removed under reducedpressure and the residue was subjected to flash column chromatography(SiO₂, hexane/ethyl acetate=100:0 to 80:20) to give the product as anoff-white solid (0.53 g, 1.9 mmol, 83% yield).

II. Preparation of 1-phenylpyrazoles of the formula (I) II.11-(4-Chlorophenyl)-3-(2-nitrobenzyloxy)pyrrazole II.1a Conversion with4-chlorophenyl bromide

A suspension consisting of 3-(2-nitrobenzyloxy)-1H-pyrazole (0.20 g,0.91 mmol), 4-chlorobromobenzene (0.14 g, 0.73 mmol), Cul (9 mg, 0.05mmol), K₂CO₃ (0.19 g, 1.4 mmol) and N,N′-dimethylcyclohexanediamine (72μL, 0.46 mmol) in 2.0 mL of toluene was heated to 100° C. for 20 h. Themixture was then cooled to rt and directly subjected to columnchromatography (SiO2, hexane/ethyl acetate=100:0 to 80:20). The productwas obtained as a yellow solid (180 mg, 0.55 mmol, 75%).

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)=8.39 (d, J=3.0 Hz, 1H); 8.13 (dd,J=1.0 Hz, J=8.0 Hz, 1H); 7.84 (dd, J=1.5 Hz, J=8.0 Hz, 1H); 7.80 (dt,J=1.5 Hz, J=7.0 Hz, 1H); 7.75 (td, J=2.5 Hz, J=9.0 Hz, 2H); 7.63 (dt,J=2.0 Hz, J=7.8 Hz, 1H); 7.50 (dd, J=2.5 Hz, J=9.0 Hz, 2H); 6.15 (d,J=2.5 Hz, 1H); 5.65 (s, 2H).

¹³C NMR (DMSO-d₆, 125 MHz): δ (ppm)=163.4; 147.5; 138.3; 133.9; 132.3;129.7; 129.4; 129.3; 129.2; 129.1; 124.7; 118.6; 94.5; 66.9.

Melting point: 140° C.

II.1b Conversion with 4-chloroiodobenzene

Following the procedure analogously to that described in 11.1a, butusing 4-chloroiodobenzene gave a yield of 54% together with 2% of theundesired regioisomer.

II.2 1-(4-Chlorophenyl)-3-(2-bromobenzyloxy-)-1H-pyrazole

A suspension consisting of 3-(2-bromobenzyloxy)-1H-pyrazole (0.20 g,0.91 mmol), 4-chloroiodobenzene (0.17 g, 0.73 mmol), Cul (9 mg, 0.05mmol), K₂CO₃ (0.05 mg, 0.38 mmol) and N,N′-dimethylcyclohexanediamine(72 μL, 0.46 mmol) in 2 mL of toluene was heated to 100° C. for 20 h.The mixture was then cooled to room temperature and directly subjectedto column chromatography (SiO₂, hexane/ethyl acetate=100:0 to 80:20).The product was obtained as a colorless solid (140 mg, 0.14 mmol, 53%yield).

¹H NMR (CDCl₃, 500 MHz): δ (ppm)=7.71 (d, J=3.0 Hz, 1H); 7.58-7.61 (m,2H); 7.56 (d, J=9.0 Hz, 2H); 7.37 (d, J=9.0 Hz, 2H); 7.34 (t, J=8.0 Hz,1H); 7.19 (dt, J=1.5 Hz, J=7.5 Hz, 1H); 5.97 (d, J=2.5 Hz, 1H); 5.39 (s,2H).

¹³C NMR (CDCl₃, 125 MHz): δ (ppm)=164.2; 136.4; 13.7; 130.7; 129.5;129.4; 129.3; 127.8; 127.5; 122.9; 119.0; 94.5; 70.3.

Melting point: 45° C.

II.3 MethylN-{2-[3′-(1-(4-chloro-phenyl)-1H-pyrazol)-yloxymethyl]-phenyl}-N-methoxycarbamate

A suspension consisting of methylN-{2-[3′-(1H-pyrazol)-yloxymethyl]-phenyl}-N-methoxycarbamate (0.25 g,0.91 mmol), 4-chlorobromobenzene (0.14 g, 0.73 mmol), Cul (9 mg, 0.05mmol), K₂CO₃ (0.05 mg, 0.38 mmol) and N,N′-dimethylcyclohexanediamine(72 μL, 0.46 mmol) in 2 mL of toluene was heated to 100° C. for 20 h.The mixture was then cooled to room temperature and directly subjectedto column chromatography (SiO₂, hexane/ethyl acetate=100:0 to 80:20).The product was obtained as an off-white oil (91 mg, 0.23 mmol, 32%yield).

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)=7.61-7.62 (m, 1H); 7.60 (d, J=2.5 Hz,1H); 7.44 (d, J=9.0 Hz, 2H); 7.30-7.36 (m, 2H); 7.26 (d, J=9.0 Hz, 2H);7.20 (t, J=7.5 Hz, 1H); 5.87 (d, J=2.5 Hz, 1H); 5.36 (s, 2H); 3.73 (s,3H); 3.72 (s, 3H).

¹³C NMR (DMSO-d₆, 125 MHz): δ (ppm)=164.2; 155.8; 138.6; 137.5; 134.8;130.4; 129.2; 128.9; 128.8; 128.5; 127.8; 127.1; 118.8; 94.5; 66.9;62.0; 53.4.

The invention claimed is:
 1. A compound of the formula (IIIa)

in which each R² is independently selected from cyano, nitro, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio and C₁-C₄-alkoxycarbonyl; each R³ is independently selected from halogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, m is 0, 1 or 2; p is 0, 1, 2 or 3, Y is nitro, a group R^(a), a group R^(b), a group R^(c) or a group R^(d),

in which R⁴ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, aryl, aryloxy, aryl-C₁-C₄-alkoxy, where the aryl groups in the three latter radicals optionally bear 1, 2, 3 or 4 substituents which are selected from halogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, and R⁵ is C₁-C₄-alkyl, C₁-C₄-haloalkyl or aryl-C₁-C₄-alkyl, where the aryl group in the latter radical optionally bears 1, 2, 3 or 4 substituents which are selected from halogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.
 2. The compound of claim 1, wherein m is
 0. 3. The compound of claim 1, wherein p is 0 or
 1. 4. The compound of claim 1, wherein p is 1 and R³ is located meta or para to the attachment point of the methylene bridge.
 5. The compound of claim 1, wherein R³ is chlorine, fluorine, C₁-C₂-alkyl or C₁-C₂-haloalkyl.
 6. The compound of claim 1, wherein R⁴ is methoxy, halomethoxy or benzyloxy.
 7. The compound of claim 1, wherein R⁵ is methyl or halomethyl.
 8. The compound of claim 1, wherein Y is nitro or a group R^(c).
 9. The compound of claim 1, wherein Y is nitro or a group R^(c) and wherein m is 0 and p is
 0. 